Myocardial infarction is a major risk for cardiac death in patients suffering from myocardial ischemia followed by reperfusion injury. During cardiac ischemia, the balance of metabolic supply and demand is broken and myocardial tissue undergoes hypoxia stress, the blood reflow (reperfusion) of the ischemic myocardium induces re-oxygenation, which results in further tissue injury and a series of intracellular responses. These responses trigger life threatening ventricular fibrillation and are accompanied by acute inflammatory responses, metabolic disorder, apoptosis, and necrosis. These may also result from cardiac dysfunction and remodelling.
Studies on anti-ischemia-reperfusion injury have long focused on preconditioning and post-conditioning cardioprotection against myocardial injury caused ischemia-reperfusion. Such studies have provided insight into the intracellular molecular signals involved in the ischemia-reperfusion injury (e.g. ROS, TNFα, polymorphonuclear leukocytes infiltration, apoptosis signals, etc.) and preconditioning and postconditioning cardioprotection (e.g. adenosine, bradykinin, and opioid peptides, SOD, etc.).
These ischemia-reperfusion-related molecular signals are potential pharmacological targets. A number of pharmacological agents including β-adrenoreceptor blockers, adenosine, cyclosporine, and nitric oxide have been studied clinical patients. However, there are no approved drugs to prevent the sudden death caused by acute myocardial infarction (heart attack).
Acacetin, obtained from the Chinese medicinal herb Tianshanxuelian, inhibits atrial IKur, IKACh, and Ito and prevents the induction of experimental atrial fibrillation in anesthetized canines after duodenal administration. Chinese Patent Application 102697769A describes the use of acacetin in an anti-ischemia/reperfusion-injury model. Chinese Patent Application No. 103058975A describes the use of acacetin in an ex vivo brain model for stroke. Clinically, an intravenous preparation is required to rescue acute atrial fibrillation or myocardial infarction. However, acacetin is water-insoluble and therefore cannot be administered intravenously in a straight forward manner.
There exists a need for water-soluble derivatives and/or water-soluble prodrugs of acacetin that can be rapidly administered intravenously to prevent sudden death from myocardial infarction.
Therefore, it is an object of the invention to provide water-soluble derivatives and/or water-soluble prodrugs of acacetin that can be rapidly administered intravenously to prevent sudden death from myocardial infarction, and methods of making and using thereof.